Human Gene Module / Chromosome X / HDAC8

HDAC8histone deacetylase 8

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
4 / 13
Rare Variants / Common Variants
7 / 3
EAGLE Score
3.7
Limited Learn More
Aliases
HDAC8, CDA07,  CDLS5,  HD8,  HDACL1,  MRXS6,  RPD3,  WTS
Associated Syndromes
Cornelia de Lange syndrome-5 (CDLS5), Cornelia de Lange syndrome 5
Chromosome Band
Xq13.1
Associated Disorders
ID
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Relevance to Autism

Mutations in the HDAC8 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-5; OMIM 300882) (Deardorff et al., 2012; Harakalova et al., 2012; Kaiser et al., 2014; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with HDAC8 mutations presented with autism spectrum disorder. An X-chromosome-wide association study of 6,873 individuals with autism from MSSNG, SSC, and SPARK (5,639 males and 1,234 females) and 8,981 controls (3,911 males and 5,070 females) in Mendes et al., 2025 identified three intronic SNPs in the HDAC8 gene that reached the significance threshold for association in meta-XWAS and both-XWAS analyses; furthermore, rare predicted damaging SNVs (<0.1% frequency in gnomAD) in the HDAC8 gene were found to have a higher frequency in ASD cases (male, female, and both sexes) from MSSNG, SSC, and SPARK compared to other family members in this report.

Molecular Function

The protein encoded by this gene belongs to class I of the histone deacetylase family. It catalyzes the deacetylation of lysine residues in the histone N-terminal tails and represses transcription in large multiprotein complexes with transcriptional co-repressors.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HDAC8 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle Deardorff MA , et al. (2012) No -
2 Support X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face Harakalova M , et al. (2012) No -
3 Support Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance Kaiser FJ , et al. (2014) No -
4 Support Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism Ansari M , et al. (2014) No -
5 Recent Recommendation Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement Kline AD , et al. (2018) No -
6 Support Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly Boonsawat P , et al. (2019) No ID, speech delay
7 Support Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder Wang L et al. (2020) Yes -
8 Support - Hiraide T et al. (2021) No -
9 Support - Pode-Shakked B et al. (2021) No -
10 Support - Miyake N et al. (2023) Yes -
11 Support - Wang J et al. (2023) Yes -
12 Support - Erica Rosina et al. (2024) No -
13 Recent Recommendation - Marla Mendes et al. (2025) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.675C>G p.Tyr225Ter stop_gained De novo - Unknown 33644862 Hiraide T et al. (2021)
c.1075C>T p.Pro359Ser missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.522C>A p.Tyr174Ter stop_gained De novo - Simplex 30842647 Boonsawat P , et al. (2019)
c.932C>T p.Thr311Met missense_variant De novo - Simplex 36973392 Miyake N et al. (2023)
c.697G>T p.Asp233Tyr missense_variant De novo - Simplex 38041506 Erica Rosina et al. (2024)
c.471T>G p.Asp157Glu missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.482del p.Tyr161SerfsTer18 frameshift_variant Familial Maternal Simplex 33023636 Wang L et al. (2020)
Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1005+24590C>T - intron_variant - - - 39706197 Marla Mendes et al. (2025)
c.1005+52717G>A - intron_variant - - - 39706197 Marla Mendes et al. (2025)
c.1006-52266C>A - intron_variant - - - 39706197 Marla Mendes et al. (2025)
SFARI Gene score
S

Syndromic

Mutations in the HDAC8 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-5; OMIM 300882) (Deardorff et al., 2012; Harakalova et al., 2012; Kaiser et al., 2014; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with HDAC8 mutations presented with autism spectrum disorder.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

1/1/2021
S
icon
S

Score remained at S

Description

Mutations in the HDAC8 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-5; OMIM 300882) (Deardorff et al., 2012; Harakalova et al., 2012; Kaiser et al., 2014; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with HDAC8 mutations presented with autism spectrum disorder.

Reports Added
[Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
10/1/2020
S
icon
S

Score remained at S

Description

Mutations in the HDAC8 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-5; OMIM 300882) (Deardorff et al., 2012; Harakalova et al., 2012; Kaiser et al., 2014; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with HDAC8 mutations presented with autism spectrum disorder.

Reports Added
[Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder2020]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Mutations in the HDAC8 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-5; OMIM 300882) (Deardorff et al., 2012; Harakalova et al., 2012; Kaiser et al., 2014; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with HDAC8 mutations presented with autism spectrum disorder.

Reports Added
[New Scoring Scheme]
4/1/2019
S
icon
S

Score remained at S

Description

Mutations in the HDAC8 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-5; OMIM 300882) (Deardorff et al., 2012; Harakalova et al., 2012; Kaiser et al., 2014; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with HDAC8 mutations presented with autism spectrum disorder.

Reports Added
[Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.2019]
Krishnan Probability Score

Score 0.43153003625512

Ranking 20762/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.92270772467946

Ranking 3006/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.92852370939365

Ranking 10936/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.4154454359874

Ranking 18508/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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